http://www.kidney-international.

org
& 2007 International Society of Nephrology

Antioxidative effects of erythropoietin

P Katavetin1, K Tungsanga1, S Eiam-Ong1 and M Nangaku2
1

Division of Nephrology, Department of Medicine, Chulalongkorn University, Bangkok, Thailand and 2Division of Nephrology and
Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan

Erythropoietin (EPO) has been shown to exert cytoprotective

effects on erythroid progenitor cells as well as various
non-erythroid cells. Experimental studies have demonstrated
the renoprotective effects of EPO in various acute and
chronic renal injury models. These protective effects have
been largely attributed to antiapoptotic signalings of EPO.
However, injured cells undergoing apoptosis are generally
too severely damaged to function properly. Therefore, simply
corrupting apoptotic pathway is unlikely to be an effective
strategy, because the remaining damaged cells may not
function appropriately, or they may eventually undergo
necrotic cell death. Recent evidences suggest that EPO also
provides cytoprotection by ameliorating oxidative stress, the
principal cellular insult. EPO may exert its antioxidative
effects directly by exploiting intracellular antioxidative
mechanisms such as heme oxygenase-1 and glutathione
peroxidase. In addition, EPO may act indirectly by inducing
iron depletion and thereby inhibiting iron-dependent
oxidative injury. Increasing red blood cells by EPO may also
indirectly reduce cellular oxidative stress, as red blood cells
are loaded with a substantial amount of antioxidative
enzymes. Further investigation regarding the mechanisms of
cellular antioxidative responses to EPO would provide a
better insight to cytoprotective action of EPO, and would
support the development of better cytoprotective drugs in
the near future.
Kidney International (2007) 72, S10S15; doi:10.1038/sj.ki.5002482
KEYWORDS: erythropoietin; cytoprotective; heme oxygenase-1; oxidative
stress

Correspondence: P Katavetin, Division of Nephrology, Department of

Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University,
Bangkok 10330, Thailand. E-mail: pkatavetin@yahoo.com
S10

Erythropoietin (EPO) is widely known as the major growth

factor for red blood cells production. The red blood
cell production-stimulating effect of EPO was well established long before it was first purified and characterized.
The first purification of human EPO from urine of aplastic
anemia patient in 1977 led to the cloning of human
EPO gene and permitted mass production of recombinant
human EPO.1
Since its introduction into clinical practice nearly two
decades ago, EPO has rapidly become a principal drug to
treat anemia. Studies over the past decade have demonstrated
that EPO has cytoprotective effects on many non-erythroid
cells. Interestingly, recent evidences suggest that EPO may
largely provide these cytoprotection by the stimulation of
antioxidative mechanisms.
EPO AND EPO RECEPTOR

EPO is a 34-kDa glycoprotein hormone composed of 165

amino acids and carbohydrate chains that are connected to
core polypeptide by three N-linked glycosylation on three
asparagine residues and O-linked glycosylation on one serine
residue. EPO is simply a code, requiring recognition by a
receptor and decoding into specific intracellular signaling
cascades to exert its biological effects. Hence, the membrane
receptor is the key to the physiological actions of circulating
EPO. EPO can act only in cells with receptor for EPO and all
actions of EPO must be mediated by the receptor.
EPO receptor presents as a homodimer on the cell
membrane.2 The binding of a single EPO molecule to
the receptor dimer induces a major conformational change in
the receptor, bringing the two Janus kinase 2 molecules, that
is tethered to cytoplasmic portion of the receptor, into close
position and thereby activating Janus kinase 2 by mutual
cross-phosphorylation. Activated Janus kinase 2 molecules
then induce phosphorylation of tyrosine residues in the
cytoplasmic domain of EPO receptor. These phosphorylated
tyrosine residues serve as a docking site attracting various
intracellular signaling molecules. These secondary signaling
molecules are subsequently activated by Janus kinase
2-mediated tyrosine phosphorylation and initiate the
downstream signal transduction pathways, such as signal
transducer and activator of transcription 5 and phosphatidylinositol 3-kinase/protein kinase B (PI3-K/Akt) pathways
(Figure 1).3,4
Kidney International (2007) 72, S10S15

P Katavetin et al.: Antioxidative effects of EPO

EPO IS A CYTOPROTECTIVE CYTOKINE

EPO

Physiologically, EPO stimulates red blood cell production

by its action on immature erythroid cells. Activation of
EPO receptor by EPO promotes the survival of erythroid
progenitor cells, which would otherwise undergo apoptosis.
Therefore, EPO is in fact a cytoprotective cytokine.
Control of erythropoiesis was once believed to be the
only physiological role of EPO. However, later studies
showed that several cells outside the hematopoietic system,
such as endothelial cells, neural cells, cardiomyocyte,
and renal cells, also express receptors for EPO.58 These
findings suggest that EPO may also provide cytoprotection
in non-hematopoietic cells and thus stimulate an interest
in EPO as a novel therapeutic agent for a number of
organs including the kidney, the major producer of EPO
circulating in the body. Experimental studies have confirmed
that EPO has neuroprotective, cardioprotective, and
renoprotective effects.

EPO

JAK2

JAK2

P JAK2

STAT5

PP
P

JAK2 P
PP

PI3-K
P

P
P

Akt
STAT5

PI3-K

FOXO,
GSK3,
etc.

PP
PP

I-
B

NF-
B

Figure 1 | Major intracellular signals activated by EPO. Binding

of EPO to EPO receptor induces phosphorylation of the signal
transducer and activator of transcription 5 transcription factors,
which then homodimerize, translocate into the nucleus, and activate
target genes. It also induces phosphorylation of phosphatidylinositol
3-kinase, which in turn phosphorylates Akt. Akt then phosphorylates
I-kB, FOXO, GSK-3b, and other molecules. I-kB phosphorylation allows
the release of the transcription factor NF-kB, which then activates
many target genes.

RENOPROTECTIVE EFFECTS OF EPO

Several in vivo studies have shown that EPO can reduce renal
injury in various animal models (Tables 1 and 2).

Table 1 | In vivo renoprotective effect of EPO: acute renal injury

Model

EPO treatment

Outcome

Reference

Rat, I/R+Nx,
(30 or 45 min)

rHuEPO 500 or 3000 U/kg i.v., 0, 24, and 48 h after

ischemia

Nemoto et al.44

Rat, I/R (45 min)

rHuEPO 3000 U/kg i.v., 24 h before ischemia

Rat, I/R (30 min)

rHuEPO 5000 U/kg i.p., 30 min before ischemia

Rat, I/R (45 min)

rHuEPO 300 U/kg i.v., 30 min before ischemia, or 5 min

before reperfusion, or 30 min after reperfusion (single
dose)

Rat, I/R (40 min)

rHuEPO 200 U/kg i.p., 0, 6, 24, 48, 72, and 96 h after

ischemia, or 4, 10, and 24 h after ischemia

Mouse I/R
(30 min)

RHuEPO 1000 U/kg s.c., 5 min before reperfusion, or

daily 3  doses before ischemia

Rat, I/R (45 min)

rHuEPO 500 U/kg i.p., 20 min before ischemia

Rat, I/R (45 min)

RHuEPO 5000 U/kg, or darbepoetin 25 mg/kg i.p., At

time of ischemia, or 6 h after reperfusion
rHuEPO 300 U/kg i.v., 5 min before resuscitation

k Mortality in I/R+Nx (45 min) treated with 3000 U/kg,

Group, Serum creatinine same as saline treated
group, Hct (48 and 72 h post-ischemia)
k Peak serum creatinine, tubular necrosis, apoptosis,
Hct not different
k Peak serum creatinine, apoptosis, tubular
regeneration, Hct not different
k Serum creatinine (6 h after reperfusion), CrCl and
urine flow (6 h after reperfusion), tubular necrosis,
apoptosis, less effective in late EPO group (30 min
after reperfusion)
k Plasma creatinine (2 and 4 day after reperfusion),
prevent downregulation of AQP and sodium
transporters
k Plasma urea and creatinine (24 h after reperfusion),
tubular necrosis MPO activity (reflecting k PMN
infiltrate), lipid peroxidation, less effective in single
dose 5 min prereperfusion group
k Serum urea and creatinine (48 h after reperfusion),
tubular necrosis, apoptosis
k Peak plasma urea and creatinine, tubular necrosis
not different, apoptosis, tubular regeneration, Hct
k Serum urea and creatinine (4 h after resuscitation)
caspase 3, 8, and 9
Serum urea and creatinine not different (6 h after LPS)

Rat, hemorrhagic
shock
Rat, endotoxic
shock
Rat, cisplatin
(7 mg/kg)
Rat, cisplatin
(6 mg/kg)
Rat, CIN
(Iothalamate)

rHuEPO 300 U/kg i.v., 30 min before LPS injection

rHuEPO 100 U/kg i.p., daily 9  dose after cisplatin
rHuEPO 100 U/kg i.p., daily 9  dose after cisplatin
rHuEPO 3000 U/kg i.v. 24 h then 600 U/kg i.v. 2 h
before CIN protocol

m CrCL and InCL (9 day after cisplatin), tubular

regeneration, Hct
m GFR and RBF (9 day after cisplatin), tubular
damages not different, tubular regeneration, Hct
Prevent k CrCL (1 day after CIN)

Yang et al.16
Vesey et al.17
Sharples et al.18

Gong et al.45
Patel et al.46

Spandou et al.19
Johnson et al.20
Abdelrahman
et al.21
Abdelrahman
et al.21
Vaziri et al.47
Bagnis et al.48
Miyoshi et al.22

CIN, contrast medium-induced nephropathy protocol (indomethacin 10 mg/kg intravenous followed by nitro-L-arginine methylester 10 mg/kg intravenous at 15 and 30 min,
then meglumine iothalamate 6 ml/kg intraarterial); CrCL, creatinine clearance; GFR, glomerular filtration rate; I/R, bilateral ischemiareperfusion injury (ischemic time in
parenthesis); Hct, hematocrit; InCL, inulin clearance; I/R+Nx, left nephrectomy and ischemiareperfusion injury to right kidney (ischemic time in parenthesis); i.p.,
intraperitoneally; i.v., intravenously; LPS, lipopolysaccharide; MPO, myeloperoxidase; PMN, polymorphonuclear; RBF, renal blood flow; rHuEPO, recombinant human
erythropoietin; s.c., subcutaneously.

Kidney International (2007) 72, S10S15

S11

P Katavetin et al.: Antioxidative effects of EPO

Table 2 | In vivo renoprotective effect of EPO: chronic renal injury

Model

EPO treatment

Outcome

Reference

Rat, 5/6 nephrectomy

Darbepoetin 0.1 mg/kg s.c., Once

weekly after renal mass reduction

Bahlmann et al.9

Rat, 5/6 nephrectomy

Darbepoetin 0.4 mg/kg s.c., Once

weekly after renal mass reduction
rHuEPO 40 U/kg s.c. thrice weekly

k Mortality, serum creatinine and urinary protein

excretion (6 week), vascular, glomerular and
tubulointerstitial damage, loss of peritubular
capillary, apoptosis, Hct not different, systolic
blood pressure
k Serum creatinine (12 week), renal scarring, Loss
of peritubular capillary VEGF expression, Hct
k Tubulointerstitial damage, loss of peritubular
capillary HO-1 expression, Hct
k Tubulointerstitial fibrosis, apoptosis, TGF-b, Hct

Rat, Dahl salt-sensitive

Rat, UUO
Rat, cyclosporine (15 mg/kg/d)

rHuEPO or carbamylated, EPO 5000 U/

kg s.c., twice weekly
rHuEPO 100 U/kg s.c., thrice weekly

Rat, doxorubicin (3 mg/kg

Darbepoetin 3 or 30 mg/kg s.c., once
follow by 2 mg/kg 2 week later) weekly 2 week after last dose of
doxorubicin
Mouse, radiation (6, 8, or 10 Gy) rHuEPO 500 or 2000 U/kg s.c., 18 and
2 h before, and 23 h after radiation

Serum creatinine and CrCL not different (4 week),

Tubulointerstitial inflammation and fibrosis, apoptosis,
tubular regeneration not different, osteopontin and
TGF-b, Hct, systolic blood pressure not different
k Serum urea and creatinine (11 week) CrCL,
tubulointerstitial fibrosis, Iron deposition urinary total
radical-trapping antioxidant capacity, Hct, systolic
blood pressure not different
m Loss of renal function

Kang et al.10
Inal et al.23
Srisawat et al.14
Lee et al.11

Noiri et al.12

Andratschke
et al.49

CrCL, creatinine clearance; Hct, hematocrit; rHuEPO, recombinant human erythropoietin; TGF, transforming growth factor; UUO, unilateral ureteral obstruction model;
VEGF, vascular endothelial growth factor.

Among many acute renal injury models, ischemiareperfusion injury is the most extensively investigated. Although
there is some heterogeneity in the protocols for inducing
ischemiareperfusion injury and in the EPO treatment
schedules, these studies provide an excellent evidence for
renoprotective effect of EPO against acute renal injury.
A recent study has demonstrated that EPO could protect
the kidney from chronic renal injury as well. Long-term
therapy of low-dose darbepoetin could reduce mortality, renal
dysfunction, and renal scarring in rats with the remnant
kidney model (5/6 nephrectomy).9 This renoprotection is not
associated with erythropoiesis effect, as hemotocrit in the
darbepoetin-treated group is similar to the saline-treated
group. Another report using standard dose darbepoetin
similarly provides renoprotection in remnant kidney model,
but occurs in association with increasing hematocrit.10 Studies
in chronic cyclosporine nephropathy and doxorubicininduced cardiorenal injury have also revealed renoprotection
by EPO.11,12 Recent preliminary reports have also found that
EPO could effectively reduce tubulointerstitial injury in the
Dahl salt-sensitive rats fed with low-salt diet and in unilateral
ureteral obstruction model.13,14
Taken together, we can conclude with reasonable confidence that EPO has cytoprotective effects on both erythroid
cells and non-erythroid cells expressing EPO receptors.

preserved pathway and present in virtually all multicellular

organisms. Although apoptosis makes some cells die, it
provides a substantial survival benefit for the organisms.
In general, cells undergoing apoptosis are severely
damaged (Figure 2a). Simply blocking apoptotic pathway is
unlikely to be an effective cytoprotective strategy, because the
remaining damaged cells may not function appropriately, or
they may eventually undergo necrotic cell death (Figure 2b).
Necrotic cell death is an irritating death. It induces
inflammation and causing additional cell damages. A study
in human fibroblast has demonstrated that reducing
apoptosis in aged cells promotes necrotic cell death and
inflammation when cells are exposed to oxidative stress.22
To be cytoprotective, EPO must have other beneficial
effects in addition to antiapoptotic signaling especially the
beneficial effects that help to reduce the cellular damages, and
thereby ameliorate cellular malfunctioning as well as necrotic
cell death (Figure 2c).
ANTIOXIDATIVE EFFECTS OF EPO

Several clinical reports have shown that EPO therapy could

reduce plasma-oxidative stress in dialysis patients.2327.These
evidences suggest that EPO may also protect cells by reducing
oxidative stress, one of the most important causes of cellular
damages (Table 3).

ANTIAPOPTOTIC SIGNALING IS NOT ENOUGH

DIRECT ANTIOXIDATIVE EFFECTS OF EPO

Cytoprotective effects of EPO have been largely attributed to

its antiapoptotic signaling.9,11,1521 However, antiapoptotic
signaling alone is unlikely to be sufficient. Apoptosis is an
active, strictly regulated process leading to a peaceful death
of the cells. Critical importance of the apoptotic process is
best demonstrated by the fact that it is an evolutionary

The direct effect of EPO on intracellular oxidative status has

been investigated in cultured renal endothelial cells.13 In
this study, EPO reduced intracellular-oxidative stress and
decreased the oxidative stress-induced cell death. These findings
suggest that EPO has meaningful direct antioxidative effects.
Interestingly, EPO significantly increased heme oxygenase-1

S12

Kidney International (2007) 72, S10S15

P Katavetin et al.: Antioxidative effects of EPO

Cellular injuries

Damaged cell

Apoptosis
Cellular injuries

Damaged cell

Malfunctioning cell

Anti-apoptosis
Necrotic cell death
Inflammation

Apoptosis

Cellular injuries
Cytoprotection

Healthy cell

Anti-apoptosis

Apoptosis

Figure 2 | Antiapoptosis is not enough. (a) Cells undergoing

apoptosis are severely damaged. (b) Simply blocking apoptotic
pathway is ineffective, because the damaged cells may not function
appropriately, or they may eventually undergo necrotic cell death.
(c) To be cytoprotective, EPO must have other beneficial effects that
help to reduce the cellular damages.

Table 3 | Antioxidative effects of EPO

EPO actions

Antioxidative effects

Direct
Increase heme
oxygenase-1

Degrade destabilized heme protein

Increase antioxidative
enzymes
Indirect
Deplete body iron
Increase young red
blood cells

Produce biliverdin and bilirubin

Enhance cellular antioxidative capacity

Reduce iron-dependent oxidative injury

Increase circulating antioxidants

Kidney International (2007) 72, S10S15

(HO-1) expression and HO-1 inhibitor, Tin protoporphyrin

(SnPP), almost completely blocked the antioxidative effects
of EPO, suggesting that upregulation of HO-1 is one of the
most important mechanisms, which EPO uses to exert its
antioxidative effects. Upregulation of HO-1 by EPO was also
demonstrated in vivo in the kidney of Dahl salt-sensitive rats.
Many studies reported have also suggested that EPO could
directly induce HO-1 expression. EPO induced heme
oxygenase activity in cultured human bone marrow erythroid
progenitor cells.28 EPO also induced HO-1 expression and
provided a cytoprotective effect in astrocytes.29 Furthermore,
EPO treatment increased monocyte HO-1 mRNA expression
as well as plasma antioxidant power in hemodialysis
patients.26
HO-1 catalyzes the rate-limiting step in heme degradation, producing carbon monoxide, free iron, and biliverdin,
which is subsequently converted to bilirubin by biliverdin
reductase.3032 HO-1 has been shown to have potent
antioxidative and antiapoptotic activities. Antioxidative
effects of HO-1 result from degradation of destabilized heme
protein and from its metabolites, biliverdin and bilirubin.
Recently, HO-1 has been demonstrated to be partly regulated
by phosphatidylinositol 3-kinase/Akt pathway, which is one
of various intracellular signals that is stimulated by EPO
(Figure 1).33,34 This finding suggests that EPO may directly
induce HO-1 expression via phosphatidylinositol 3-kinase/
Akt pathway.35 Further studies are clearly warranted to
examine direct link between EPO and HO-1.
Besides HO-1 induction, EPO may exert its antioxidative
effects by induction of antioxidative enzymes, such as
superoxide dismutase, catalase, and glutathione peroxidase.
EPO has been reported to increase glutathione peroxidase
activity in cultured murine astroglial cells and in brain tissue
of experimental animals.36,37 Additional studies to delineate
fully direct antioxidative mechanisms of EPO are indicated.
INDIRECT ANTIOXIDATIVE EFFECTS OF EPO

At least two indirect antioxidative effects of EPO have been

proposed. These effects are indirect because they are
mediated by action of EPO on erythroid progenitor cells,
not on the cells to be protected.
First, EPO may indirectly provide antioxidative effect by
depleting body iron.38 Iron is a major catalyst for free radical
reaction, especially the Fenton reaction that results in highly
reactive hydroxyl radical. Therefore, depleting body iron is
likely to limit highly reactive free radical production.
Increasing red blood cell production by EPO treatment
induces iron depletion, which then helps to ameliorate irondependent oxidative injury. An experimental study in
premature rabbits demonstrated that EPO treatment decreased plasma iron, and iron saturation of transferrin,
whereas increased plasma and bronchoalveolar lavage fluid
antioxidative capacity.39 Preterm infants who received EPO
treatment had significantly reduced serum ferritin accompanied by reduced serum lipid peroxidation.40 EPO treatment did not change the activities of erythrocyte
S13

P Katavetin et al.: Antioxidative effects of EPO

antioxidative enzymes (superoxide dismutase, catalase and

glutathione peroxidase), suggesting that antioxidative effects
of EPO in these preterm infants may be mediated by iron
depletion.
Second, EPO may also indirectly reduce cellular oxidative
stress by increasing number of circulating young red blood
cells.25 Young red blood cells are loaded with substantial
amount of antioxidative enzymes and these protective
enzymes in red cells decrease their activities over time.41
Clinical reports have confirmed that EPO therapy could
increase level of erythrocyte antioxidative enzymes.23,25,42,43
As mature red blood cells lack de novo protein synthesis, the
increasing erythrocyte antioxidative enzymes by EPO is likely
to result from increasing circulating young red cells, which
contain high level of the enzymes.

10.

11.

12.
13.

14.

15.
16.

17.
18.

CONCLUSION

Overwhelming data confirmed that EPO has cytoprotective

effects on non-erythroid cells. Emerging evidences indicate
that EPO may mainly protect cells by exerting antioxidative
actions, either directly or indirectly. Further investigation
regarding the mechanisms underlying the antioxidative
effects of EPO would provide a critical insight to cytoprotective action of EPO. An understanding of these mechanisms
would support the development of new EPO-related drugs
that have potent antioxidative effects and therefore effective
for cytoprotection in the near future.

19.

20.

21.

22.

23.

DISCLOSURE

Pisut Katavetin has received lecture fees from Kirin Brewery Co. Ltd.
Kriang Tungsanga has received lecture fees from Roche Thailand,
Janssen & Janssen Thailand, and Fresenius Kabi Thailand. He has
received consulting fees from Janssen and the Ketosteril Asia-Pacific
Advisory Board meeting and grant support from Project CERA.
Somchai Eiam-Ong has nothing to disclose. Masaomi Nangaku has
received lecture fees and grant support from Kirin Brewery Co. Ltd.

24.

REFERENCES

27.

1. Miyake T, Kung CK, Goldwasser E. Purification of human erythropoietin.

J Biol Chem 1977; 252: 55585564.
2. Livnah O, Stura EA, Middleton SA et al. Crystallographic evidence for
preformed dimers of erythropoietin receptor before ligand activation.
Science 1999; 283: 987990.
3. Silva M, Benito A, Sanz C et al. Erythropoietin can induce the expression
of bcl-x(L) through Stat5 in erythropoietin-dependent progenitor cell
lines. J Biol Chem 1999; 274: 2216522169.
4. Damen JE, Mui AL, Puil L et al. Phosphatidylinositol 3-kinase associates,
via its Src homology 2 domains, with the activated erythropoietin
receptor. Blood 1993; 81: 32043210.
5. Masuda S, Nagao M, Takahata K et al. Functional erythropoietin receptor
of the cells with neural characteristics. Comparison with receptor
properties of erythroid cells. J Biol Chem 1993; 268: 1120811216.
6. Tramontano AF, Muniyappa R, Black AD et al. Erythropoietin protects
cardiac myocytes from hypoxia-induced apoptosis through an
Akt-dependent pathway. Biochem Biophys Res Commun 2003; 308:
990994.
7. Westenfelder C, Biddle DL, Baranowski RL. Human, rat, and mouse kidney
cells express functional erythropoietin receptors. Kidney Int 1999; 55: 808820.
8. Anagnostou A, Lee ES, Kessimian N et al. Erythropoietin has a mitogenic
and positive chemotactic effect on endothelial cells. Proc Natl Acad Sci
USA 1990; 87: 59785982.
9. Bahlmann FH, Song R, Boehm SM et al. Low-dose therapy with the
long-acting erythropoietin analogue darbepoetin alpha persistently
activates endothelial Akt and attenuates progressive organ failure.
Circulation 2004; 110: 10061012.

S14

25.

26.

28.

29.

30.
31.
32.
33.

34.
35.

36.

Kang DH, Park EY, Yu ES et al. Renoprotective effect of erythropoietin

(EPO): possibly via an amelioration of renal hypoxia with stimulation of
angiogenesis in the kidney. Kidney Int 2005; 67: 1683.
Lee SH, Li C, Lim SW et al. Attenuation of interstitial inflammation and
fibrosis by recombinant human erythropoietin in chronic cyclosporine
nephropathy. Am J Nephrol 2005; 25: 6476.
Noiri E, Nagano N, Negishi K et al. Efficacy of darbepoetin in doxorubicininduced cardiorenal injury in rats. Nephron Exp Nephrol 2006; 104: E6E14.
Katavetin P, Inagi R, Miyata T et al. Erythropoietin induces heme
oxygenase-1 expression and attenuates oxidative stress. Biochem Biophys
Res Commun 2007; 359: 928934.
Srisawat N, Manotham K, Kanjanabuch T et al. Amelioration of
tubulointerstitial fibrosis by erythropoietin and carbamylated
erythropoietin treatment. J Am Soc Nephrol 2006; 17 PUB127.
Fishbane S, Ragolia L, Palaia T et al. Cytoprotection by darbepoetin/epoetin
alfa in pig tubular and mouse mesangial cells. Kidney Int 2004; 65: 452458.
Yang CW, Li C, Jung JY et al. Preconditioning with erythropoietin protects
against subsequent ischemiareperfusion injury in rat kidney. FASEB J
2003; 17: 17541755.
Vesey DA, Cheung C, Pat B et al. Erythropoietin protects against
ischaemic acute renal injury. Nephrol Dial Transplant 2004; 19: 348355.
Sharples EJ, Patel N, Brown P et al. Erythropoietin protects the kidney
against the injury and dysfunction caused by ischemiareperfusion. J Am
Soc Nephrol 2004; 15: 21152124.
Spandou E, Tsouchnikas I, Karkavelas G et al. Erythropoietin attenuates
renal injury in experimental acute renal failure ischaemic/reperfusion
model. Nephrol Dial Transplant 2006; 21: 330336.
Johnson DW, Pat B, Vesey DA et al. Delayed administration of
darbepoetin or erythropoietin protects against ischemic acute renal
injury and failure. Kidney Int 2006; 69: 18061813.
Abdelrahman M, Sharples EJ, McDonald MC et al. Erythropoietin
attenuates the tissue injury associated with hemorrhagic shock and
myocardial ischemia. Shock 2004; 22: 6369.
Miyoshi N, Oubrahim H, Chock PB, Stadtman ER. Age-dependent cell
death and the role of ATP in hydrogen peroxide-induced apoptosis and
necrosis. Proc Natl Acad Sci USA 2006; 103: 17271731.
Inal M, Kanbak G, Sen S et al. Antioxidant status and lipid peroxidation in
hemodialysis patients undergoing erythropoietin and erythropoietinvitamin E combined therapy. Free Radic Res 1999; 31: 211216.
Usberti M, Gerardi G, Bufano G et al. Effects of erythropoietin and vitamin
E-modified membrane on plasma oxidative stress markers and anemia of
hemodialyzed patients. Am J Kidney Dis 2002; 40: 590599.
Mimic-Oka J, Simic T, Djukanovic L. Epoetin treatment improves red
blood cell and plasma antioxidant capacity in hemodialysis patients. Ren
Fail 2002; 24: 7787.
Calo LA, Stanic L, Davis PA et al. Effect of epoetin on HO-1 mRNA level
and plasma antioxidants in hemodialysis patients. Int J Clin Pharmacol
Ther 2003; 41: 187192.
Siems W, Carluccio F, Radenkovic S et al. Oxidative stress in renal anemia
of hemodialysis patients is mitigated by epoetin treatment. Kidney Blood
Press Res 2005; 28: 295301.
Abraham NG, Nelson JC, Ahmed T et al. Erythropoietin controls heme
metabolic enzymes in normal human bone marrow culture. Exp Hematol
1989; 17: 908913.
Diaz Z, Assaraf MI, Miller Jr WH, Schipper HM. Astroglial cytoprotection by
erythropoietin pre-conditioning: implications for ischemic and
degenerative CNS disorders. J Neurochem 2005; 93: 392402.
Platt JL, Nath KA. Heme oxygenase: protective gene or Trojan horse.
Nat Med 1998; 4: 13641365.
Abraham NG, Kappas A. Heme oxygenase and the cardiovascular-renal
system. Free Radic Biol Med 2005; 39: 125.
Deshane J, Wright M, Agarwal A. Heme oxygenase-1 expression in
disease states. Acta Biochim Pol 2005; 52: 273284.
Salinas M, Wang J, Rosa de Sagarra M et al. Protein kinase Akt/PKB
phosphorylates heme oxygenase-1 in vitro and in vivo. FEBS Lett 2004;
578: 9094.
Lee TS, Chang CC, Zhu Y, Shyy JY. Simvastatin induces heme oxygenase-1:
a novel mechanism of vessel protection. Circulation 2004; 110: 12961302.
Calo LA, Davis PA, Piccoli A, Pessina AC. A role for heme oxygenase-1
in the antioxidant and antiapoptotic effects of erythropoietin: the start
of a good news/bad news story? Nephron Physiol 2006; 103: P107P111.
Genc S, Akhisaroglu M, Kuralay F, Genc K. Erythropoietin restores
glutathione peroxidase activity in 1-methyl-4-phenyl-1,2,5,6tetrahydropyridine-induced neurotoxicity in C57BL mice and stimulates
murine astroglial glutathione peroxidase production in vitro. Neurosci Lett
2002; 321: 7376.
Kidney International (2007) 72, S10S15

P Katavetin et al.: Antioxidative effects of EPO

37.

38.

39.

40.

41.

42.

Kumral A, Gonenc S, Acikgoz O et al. Erythropoietin increases glutathione

peroxidase enzyme activity and decreases lipid peroxidation levels
in hypoxic-ischemic brain injury in neonatal rats. Biol Neonate 2005;
87: 1518.
Bailey DM, Robach P, Thomsen JJ, Lundby C. Erythropoietin depletes iron
stores: antioxidant neuroprotection for ischemic stroke? Stroke 2006; 37:
2453.
Bany-Mohammed FM, Slivka S, Hallman M. Recombinant human
erythropoietin: possible role as an antioxidant in premature rabbits.
Pediatr Res 1996; 40: 381387.
Akisu M, Tuzun S, Arslanoglu S et al. Effect of recombinant human
erythropoietin administration on lipid peroxidation and antioxidant
enzyme(s) activities in preterm infants. Acta Med Okayama 2001; 55:
357362.
Glass GA, Gershon D. Decreased enzymic protection and increased
sensitivity to oxidative damage in erythrocytes as a function of cell and
donor aging. Biochem J 1984; 218: 531537.
Delmas-Beauvieux MC, Combe C, Peuchant E et al. Evaluation of red
blood cell lipoperoxidation in hemodialysed patients during
erythropoietin therapy supplemented or not with iron. Nephron 1995; 69:
404410.

Kidney International (2007) 72, S10S15

43.

44.

45.

46.

47.
48.

49.

Canestrari F, Buoncristiani U, Galli F et al. Redox state, antioxidative

activity and lipid peroxidation in erythrocytes and plasma of chronic
ambulatory peritoneal dialysis patients. Clin Chim Acta 1995; 234:
127136.
Nemoto T, Yokota N, Keane WF, Rabb H. Recombinant erythropoietin
rapidly treats anemia in ischemic acute renal failure. Kidney Int 2001; 59:
246251.
Gong H, Wang W, Kwon TH et al. EPO and alpha-MSH prevent ischemia/
reperfusion-induced down-regulation of AQPs and sodium transporters
in rat kidney. Kidney Int 2004; 66: 683695.
Patel NS, Sharples EJ, Cuzzocrea S et al. Pretreatment with EPO reduces
the injury and dysfunction caused by ischemia/reperfusion in the mouse
kidney in vivo. Kidney Int 2004; 66: 983989.
Vaziri ND, Zhou XJ, Liao SY. Erythropoietin enhances recovery from
cisplatin-induced acute renal failure. Am J Physiol 1994; 266: F360F366.
Bagnis C, Beaufils H, Jacquiaud C et al. Erythropoietin enhances recovery
after cisplatin-induced acute renal failure in the rat. Nephrol Dial
Transplant 2001; 16: 932938.
Andratschke N, Schnaitera A, Weber WA et al. Preclinical evaluation of
erythropoietin administration in a model of radiation-induced kidney
dysfunction. Int J Radiat Oncol Biol Phys 2006; 64: 15131518.

S15